Phototherapy (PT) relates to the use of electromagnetic radiation to stimulate biological phenomena that promotes healing or aesthetic changes in tissue. In the early 1960s, European scientists began studies on the use of low energy light beams of specific wavelengths and frequencies to treat damaged cell tissue by altering cellular functions and enhancing healing non-destructively. Low level laser therapy (LLLT) followed by light emitting diode (LED) therapy were developed and applied to the treatment of dermatological, musculoskeletal, soft tissue and neurological conditions. It is well documented now that a wide range of disorders of biological tissue or their symptoms have been treated by PT [1-26], including but not limited to acute and chronic musculoskeletal conditions such as arthritis, degenerative disc and joint diseases, bone spurs, back and joint pain, tendonitis, muscle pain and stiffness and myofascial pain. PT has also been used to treat such conditions as post surgical complications such as swelling, inflammation, scarring and stiffness; acute trauma and chronic post-traumatic conditions in the soft tissues and bones including sprains, strains, wounds, whiplash; repetitive strain injuries such as carpal tunnel syndrome, tennis and golfer's elbow; neurological and neuromuscular conditions, dermatological conditions such as burns, acne, herpes simplex, psoriasis, skin cancer and ulcers including infected or non-infected chronic ulcers of different etiology such as venous ulcers, diabetic ulcers, decubitus ulcers, pressure sores, burns and post-traumatic ulcers, as well as seasonal depression. PT has also been reported to reduce wrinkles, and induce relaxation.
In a study funded by a NASA Small Business Innovation Research contract, Whelan and his team [1] studied the influence of PT treatment using LEDs on cells grown in culture, on ischemic and diabetic wounds in rat models, and on acute and chronic wounds in humans. Their studies utilized a variety of LED wavelengths, power, and energy density to identify conditions for biostimulation of different tissues. They found that PT using LEDs produced in vitro increases of cell growth of 140-200% in mouse-derived fibroblasts, rat-derived osteoblasts, and rat-derived skeletal muscle cells, and increases in growth of 155-171% of normal human epithelial cells. PT using LEDs produced improvement of greater than 40% in musculoskeletal training injuries in Navy SEAL team members, and decreased wound healing time in crew members aboard a U.S. Naval submarine. Lacerations doubled their healing rate when exposed to the LED light. Some injuries treated with the LEDs healed in just seven days, compared to unexposed injuries that took two weeks. Whelan and colleagues also found that lights help wounds that are normally very difficult to heal such as diabetic skin ulcers, serious burns and the severe oral sores caused by chemotherapy and radiation [1]. Their investigations take place in laboratory and human trials, approved by the U.S. Food and Drug Administration.
Recent in vivo and clinical studies suggest that lasers can induce phenomena in injured tissues which promote acceleration of recovery after acute trauma [19-21]. Faster edema reduction and lymph flow enhancement were observed in laser-treated animals after surgery in mice [20] and rat arthritis [21]. Faster edema resolution and regeneration at cut blood and lymph vessels were observed in the laser treated group in the study performed on 600 mice [20]. It was also found that laser light induced local microcirculation improvement resulting in relief of local spasm of arteriolar and venular vessels, intensification of blood flow in nutritional capillaries, anastomosis opening and activation of neoangiogenesis [17].
One of the best documented PT treatments that has been in routine use in hospitals for many years, is the treatment of hyperbilirubinemia, a condition where there is an elevated level of bilirubin in an infant's blood. Normally bilirubin is conjugated within the liver and excreted. However, during the initial neonatal period the infant's liver may be too immature to conjugate bilirubin. Phototherapy is the treatment of choice for neonatal hyperbilirubinemia and has been used for many years with no known negative side effects. Bilirubin has absorption bands in the visible wavelengths region of the spectrum between 400 and 500 nm with a maximum absorption approximately in the 450-460 nm region. There is a clear dose-response relationship as demonstrated by a decrease in the bilirubin level proportional to the level of exposure to light.
Ultraviolet (UV) radiation has been used to treat dermatological diseases such as psoriasis since the early 20th century. However, UV radiation produces ionization and therefore has the potential to damage biomolecules. As a result, the dosage or exposure must be controlled carefully to avoid damage to biological tissue.
There are also reports on successful treatment of aesthetic problems, using PT. Particularly, decreasing of cellulites and wrinkles when treated with radiation of selected wavelength in the visible and NIR part of the spectrum has been reported.
Quite recently, the combined approach of using light as a very specific mechanism to trigger the effects of specialized pharmaceuticals has been developed. This approach, called photodynamic therapy (PDT) uses certain drugs, which for example are preferably adsorbed at tumors which, when irradiated with visible light, initiate cytotoxic photochemical reactions that produce local tumor necrosis. Another recent application of PDT is the use of photosensitizer drugs that exert an anti-microbial effect only when irradiated with light of a certain wavelength. Activated with light, the drug produces potent anti-microbial molecules that kill neighboring micro-organisms, mainly by physically damaging their cytoplasmic membranes [26]. Most photosensitive substances used in photodynamic therapy are activated at wavelengths between 300 nm and 800 nm. Light emitting diodes are typically used to treat surface conditions while a laser coupled to a fiber optic catheter is often used to treat sub-surface regions. Subcutaneous tissue may also be treated using an external light source that emits light at a wavelength that penetrates the cutaneous layer overlying the tissue to be treated.
Currently, therapeutic benefits have been reported for wavelengths ranging from UV radiation to the near-infrared (N-IR) region of the spectrum [1-26]. Current research suggests that when phototherapy is used within this wide range of wavelengths for treatment of a particular medical condition, light may interact with tissue at the molecular, cellular, and organism levels. At a molecular level, light therapy methods are based on photochemical conversion of non-specialized photoacceptor molecules (i.e. molecules that can adsorb light at certain wavelengths but are not incorporated into the light reception organs). These non-specialized photoacceptors can be cell native components or can be introduced artificially, as in a case of photodynamic therapy. In the case of adsorption of light of a specific wavelength by a native photoacceptor with corresponding excitation of their electronic states, the cellular metabolism can be altered [2,3]. More specifically, Karu [2,3, 15] suggested that irradiation of isolated mitochondria induces changes in cellular homeostasis, which entail a cascade of reactions, and proposed a number of the components of the respiratory chain that can trigger the reactions. Currently it is speculated, that the biological effects of low level visible light is through photochemistry (probably electronic excitations of enzymes [2,3,15]), and the biological effect of infrared radiation is due to photophysical effects on the cell membrane level, mainly through molecular rotation and vibrations modifying the ion channels in membranes [13] that influence the total cascade of molecular events and leads to biostimulation.
In order to identify a photoacceptor molecule, experiments on cell cultures were performed to obtained action spectra, which is a plot of the relative efficiencies of different wavelengths of light in causing a biological response (such as proliferation, migration, collagen synthesis, autocrine production of growth factors etc.) [ 1,2,3]. It is known [2] that within certain limits an action spectrum follows the absorption spectrum of the photoacceptor molecule. By comparison the obtained absorption spectrum of cells with spectral data for particular metal-ligand complexes corresponding to different candidate photoacceptors, the enzymes, participating in the biological response, can be identified. As no action spectra for clinical effects have yet been produced, action spectra for cellular effects are currently used to recommend optimal light wavelengths for clinical applications. Experiments on different cell cultures (microbe and mammalian) have revealed the ranges of wavelengths (360-440 nm, 630-680 nm, 740-760 nm, 810-840 nm) where known photoinduced phenomena are observed [2,3].
Ideally, in clinical applications photons of a particular wavelength excite photoacceptor molecules providing the desired biological response. The light should generally be capable of reaching not only superficial tissue but also deeper layers. In order to arrive at a particular treatment protocol, in addition to the action spectra of various photobiological effects and absorption spectra of photoacceptor molecules responsible for these photobiological effects, the following data can also be taken into account: (1) absorption spectra of the surrounding tissue light adsorbing molecules, and (2) wavelength penetration depth data.
The light absorbed by biological tissue depends on the wavelength of the light and the properties of the irradiated tissue. Factors such as reflectivity, absorption coefficient, and scattering coefficient determine the dose versus depth distribution of the incident light. In biological tissue, hemoglobin is a strong absorber of light in the visible region of the spectrum while water has several strong absorption bands in the IR region. Thus the absorption bands of these two molecules should be considered in selecting a wavelength that will pass substantially unattenuated through tissue to deliver the desired radiation to the area to be treated. The dose will also vary as a function of depth due to absorption.
In general, each condition being treated by phototherapy may utilize unique settings of treatment parameters such as wavelength, monochromaticity, bandwidth, pulse frequency, pulse duration, power intensity, dose, and three-dimensional light distribution in the tissue. An extensive summary of suggested protocols developed for treatment of a wide range of disorders is provided in the patent of Salansky and Filonenko [7].
For different applications, different wavelengths might be optimal. Regarding the DNA and RNA synthesis in cell-level experiments, Tiina Karu [2,3] suggested that laser emission at 820-830 nm, 760 nm and 680 nm would be sufficient for low power light therapy. According to the patent by Salansky and Filonenko [7] clinical studies reveal that wavelengths in the range from 400 to 10,000 nm may be used for PT, preferably from 500 to 2,000 nm. There appears to be some optimal wavelength range to induce a particular photoeffect for certain healing phenomenon. For example, according to [7], light having a wavelength from 600 to 700 nm, preferably from 630-680 nm, may be used for wound and ulcer healing. For chronic soft tissue pathology, monochromatic light in the near infrared wavelength range (800-1,100) is more suitable [7]. In general, different researchers in the area of phototherapy have used light at the following wavelengths (nm) for phototherapy: 470, 565, 585, 595, 620, 635, 645, 655, 660, 700, 830, 840, 880, 910, 920, 940.
A phototherapeutic dose is determined by a light intensity (power density) and an exposure time. For stimulating healing of chronic ulcers or wounds, a power density has been reported in the range from 0.2 to 10 mW/cm2. For ulcers or wounds in the acute inflammatory stage the range was from 10 to 30 mW/cm2 and for infected wounds the range was from 50 to 80 mW/cm2 [7]. Reported doses for photobiomodulation are in the range of from 0.1 to 20 J/cm2 [7]. For stimulating healing of chronic ulcers or wounds doses may preferably be in the range of from 0.05 to 0.2 J/cm2, for ulcers or wounds in the acute inflammatory stage a preferred range is from 2 to 5 J/cm2 and for infected wounds a preferred range is from 3.0 to 7.0 J/cm2.
It has been also reported that the interaction between living cells and pulsed electromagnetic waves depends on the wavelength as well as pulse frequency and duration. Pulse repetition rates within the range 1,000-10,000 Hz with different pulse durations (milliseconds to microseconds) can be used to change average power [7]. Low range frequencies of 0 to 200 Hz may stimulate the release of key neurotransmitters and/or neurohormones [7]. It has been theorized that these frequencies may correspond to some basic electromagnetic oscillation frequencies in the peripheral and central nervous system. Once released these neurotransmitters and/or neurohormones can modulate inflammation, pain or other body responses.
Optical protocols have been developed based on the parameters described above. Protocols for a wide variety of disorders have been developed for laser diodes, superluminescent diodes, and LED single probes or clusters, for example by Salansky [7]. They have been used in the ‘Pain & Injury Rehabilitation Centers’, Toronto, Canada. For example, the specificity of protocols for musculoskeletal conditions depends on (i) the stage of inflammatory process (acute, subacute inflammation, chronic inflammation with or without flare-up of preexisting pathological condition); (ii) localization of soft tissue affected areas, muscle spasm, tender and trigger points. For skin conditions, choice of a protocol can depend on the stage of inflammation (acute or chronic inflammation, presence or absence of bacteria contamination). Protocols developed by Salansky for laser diodes usually take about two to six minutes; it rarely exceeds ten minutes. Whelan [1] used LED therapy at 680, 730, and 880 nm wavelengths simultaneously for about 30 minutes per treatment in human trials. In general, the duration of treatment depends on the power of a light source, with longer times being used with sources of lower power density.
The areas of phototherapy and photodynamic therapy are undergoing rapid development. Yet, a detailed understanding of the mechanism that produces the beneficial effect has not been achieved in many treatments.
There are several sources of radiation currently used for phototherapy and aesthetic applications. The He—Ne laser (λ=632.8 nm) was the first laser to be used in clinical and research applications from the sixties to mid-eighties, when semiconductor lasers and light emitting diodes became available [3]. “Cold” lasers produce a lower average power of 100 milliwatts or less. Lasers are widely used in phototherapy because they produce narrow-band monochromatic, coherent, polarized light with a wide range of powers and intensities. High-power is used in surgery and mid-power is used in dermatology to treat, for example, telangiectasia, port-wine stains. Lasers must be used cautiously to avoid or achieve limited heating of tissues except when higher powers are desired for use in surgery, dermatology, etc. Coherence and polarization are the two main features that distinguish light from lasers from other sources of monochromatic light. But, laser beams quickly lose coherence and polarization due to scattering upon entering tissue. So, many of the reputed advantages due to these properties of laser beams may be lost. A common laser beam source in current PT applications is the semiconductor laser diodes (LD), where light emission arises from recombination of electron and holes injected into a lasing cavity. Recently, vertical cavity surface emitting lasers had been also suggested for use in PT devices [27]. Although phototherapy began with the use of low level lasers, several other light sources have been used since that time, that are briefly outlined below.
Light emitting diodes are semiconductor devices in which a point source of light is produced when current carriers combine at a pn junction. The emission is spontaneous and the output power is typically lower than that from diode lasers, reflecting the use of lower operating currents. Generally LEDs are less expensive than diode lasers and can operate at shorter wavelength without the rapid degradation that occurs with visible-wavelength laser diodes. Light from an LED is an incoherent (spontaneous) emission, as distinct from the coherent (stimulated) emission produced by lasers. LEDs have undergone a major growth spurt in recent years. The first LED units available for purchase for use in PT in the equine industry [3] used 8mW peak power per diode. At this writing, devices are commercially available which use a cluster of LEDs with 150 mW peak power per diode. Another PT light source, superluminous diodes are a compromise between a laser and a LED, which is operated at high drive currents characteristic of diode lasers, but lack the cavity feedback mechanisms that produce stimulated emission. It is used when high-power output is desired, but coherent emission is not needed. Both LEDs and LDs are three-dimensional semiconductor structures that produce point sources of light.
The conventional light sources used in photobiological studies as well as in phototherapy are incandescent lamps, fluorescent lamps, and electric arcs. It is generally necessary to monochromatize their continuous spectrum. This is accomplished with either a monochromator (with bandwidth 5-10 nm) or filters. Conventional light sources are usually used in laboratory work for recording of action and absorption spectra or obtaining a wavelength which is not emitted by available lasers or LEDs [3].
Conventional PT devices (based on LD and LEDs) are generally configured into a hand-held probe with a single or a few point sources of light or a large stationary probe having an array of lasers for clinical use. Since LDs and LED sources of radiation are small three-dimensional semiconductor devices that act as point sources of light, they cannot provide uniform doses of radiation over the treated surface of the body. To solve this problem, light diffusers are used. When several specific wavelengths are required, several types of laser diodes or LEDs with different emission wavelengths are used within an array, making it yet more difficult to achieve uniform irradiation of a particular wave length. LD or LEDs array mounted on a substrate possess its own circuitry with wiring required to each individual LED or LD. LED arrays also generally require a cooling mechanism.